Homeostasis of the eye, as in tissues elsewhere in the body, depends on the presence of normal vasculature, extra cellular matrix, and various cell types. If homeostasis is disturbed by infection, inflammation, or metabolic disease, visual function becomes impaired. The end result of these conditions is often fibrosis.
The posterior segment of the eye consists of structures behind the lens; the interior of the back of the eye is filled with vitreous, a viscoelastic material consisting largely of water, collagen, and hyaluronic acid. The vitreous serves as a shock absorber, among other things, for the retina, the most posterior tissue in the eye. In addition, the vitreous can provide scaffolding over which glial and endothelial cells migrate from their normal intraretinal position anteriorly over the retinal surface and/or into the vitreous in certain disease states (e.g., diabetes, proliferative vitreoretinopathy, retinopathy of prematurity). The retina consists of multiple layers of neurons, blood vessels, extra cellular matrix (ECM), and various resident and transient cells such as glial cells and monocytes. The vascular supply of the retina consists of the retinal blood vessels (found in three layers on the innermost portion of the retina) and the choriocapillaris (a rich vascular plexus found in the outermost portion of the retina). The photoreceptors rest on a monolayer of cells, the retinal pigmented epithelium (RPE). The RPE rests on a collagenous basement membrane (Bruch membrane), and directly beneath this structure flows the choriocapillaris, providing blood supply for the outer third of the retina. Although there is a blood-retina barrier and relative immune privilege in this part of the eye, normal inflammatory responses to irritation and hypoxia can be quite robust and can lead to much of the pathology observed in diseases that decrease vision.
The leading cause of vision loss in Americans over the age of 65 is macular degeneration (MD); 12-15 million Americans over the age of 65 have this disease and 10%-15% of them will lose central vision as a direct effect of neovascularization and fibrosis.
Advances in therapeutic options available to treat neovascular macular degeneration have provided some benefit to small subsets of patients with this disease (19, 20). Most drugs currently in clinical trials or approved for treating MD-associated neovascularization are directed at inhibiting promoters of angiogenesis, such as VEGF. Unfortunately, current thinking holds that inhibiting angiogenic cytokines does not address the underlying pathophysiology—ischemia and inflammatory stimuli, and that efforts to minimize sub- and epiretinal fibrosis have met with limited success and that, in any event, such efforts would represent a therapeutic intervention occurring too late to rescue vision, since such scarring would have already led to photoreceptor death.
The leading cause of visual loss for Americans under the age of 65 is diabetes; 6%-8% of the American population is diabetic, and 40,000 patients each year suffer visual loss from complications of the disease, often as a result of retinal edema or neovascularization. Virtually every diabetic has some form of DR after 20 years of the disease. Ischemia occurs as a result of the diabetic microvasculopathy that includes pericyte cell death, microaneurysms, intraretinal microvascular abnormalities, altered vascular permeability, and macular edema. As the hypoxia increases, neovascularization can occur, leading to intraretinal, subhyaloid (between the retinal surface and posterior vitreous base) and vitreous hemorrhage. These proliferating blood vessels are accompanied by fibrosis that occurs as a consequence of glial cell activation and proliferation (gliosis). As abnormal vessels continue to proliferate on the retinal surface, they can extend into the vitreous and contract, causing traction on the retinal surface and leading to retinal detachment, a dreaded complication of proliferative DR. Retinal neovascularization and associated gliosis and fibrosis are also observed in ROP and as a complication of surgery to treat retinal detachment. Surgical intervention and laser obliteration of the peripheral retina (to decrease the metabolic demand and thereby match up supply and demand) are the current treatments and are of limited benefit.
Nowhere in the literature is the case made that mast cells are the source of any of these angiogenic and pro-fibrotic factors that cause diseases of the retina and vitreous. Indeed, the current state of the art in ophthalmology is that mast cells are not found in the privileged space of the retina or vitreous.